With increasing life expectance of humans in the industrialized countries age-correlated dementia increasingly becomes a social and economic problem. Among the different forms of dementia, Alzheimer's disease (AD) is the most common cause. Although recent research unraveled detailed molecular mechanisms of AD pathogenesis, the cause of the sporadic form is widely unknown, most likely because of its heterogeneous nature. Two proteins have been established as central pathomolecules, the plaque forming amyloid β, and the tangle composing hyperphosphorylated tau. Notably, the involvement of the β2-adrenergic receptor (β2-AR) in processing precursor proteins of amyloid-β was recently reported [1]. Activation of β2-AR resulted in enhanced plaque formation. The most obvious risk factor of AD is ageing. Other risk factors include hypercholesterolemia, hypertension, atherosclerosis, coronary heart disease, smoking, obesity, and type 2 diabetes [2, 3]. There is evidence that the cognitive decline and central nervous system pathology may be secondary to pathologic alterations in the vasculature of AD patients' brain [4]. Epidemiological, clinical pharmacological, neuroimaging and pathological studies support the notion that vascular disorders are the primary cause of sporadic, non-genetic AD.
The second most common form of dementia in older adults is vascular dementia. Often AD and vascular dementia coexist in older patients. The causes of this form of dementia are different, often diffuse disorders all leading to vascular lesions. People who suffered from ischemic stroke developed dementia with a four-fold higher incidence than controls [5].
Adrenergic receptors (AR) belong to the superfamily of G protein-coupled receptors (GPCR), the most important cell surface receptors. AR mediate the action of catecholamines at the cellular level. They regulate numerous cellular functions such as muscle contraction including vascular tone. Circulating agonistic autoantibodies (agAAB) directed against AR have been found to be associated with different, mainly cardiovascular diseases in humans. It was shown that patients suffering from hypertension may contain agAAB predominantly to the α1-adrenergic receptor (α1-AR) or to the angiotensin II type 1 receptor [6-8]. There is growing evidence that these agAAB are of pathogenic relevance [9, 10]. In animal models it was shown that agAAB to the α1-AR induce cellular remodeling and cause vascular damages [11-13]. Based on evidences of agAAB potency to cause vascular damages and of the crucial role of vascular disorders in AD and vascular dementia, investigation was undertaken to interrogate the involvement of GPCR related autoimmune mechanisms in this disease.
The invention discloses for the first time the presence of agAAB to the α1-AR and β2-adrenergic receptor (β2-AR) in patients with moderate to mild dementia of the AD and vascular type.